Latent HIV-1 reservoirs are established early in infection and persist in long-lived cell types. These cellular reservoirs remain our greatest challenge to curing HIV disease in that they are resistant to highly active antiretroviral therapy (HAART). New evidence suggests that CD4+CD25+FoxP3+ Regulatory T (Treg) cells are a newly defined reservoir of latent HIV infection. The mechanisms underlying establishment of latency and viral reactivation in Treg cells are undefined. We have developed a robust model of primary Treg cell HIV infection that mimics the properties of HIV reservoirs in vivo. We propose to utilize this model system in combination with cells isolated from HIV+ patients to define the mechanisms responsible for induction of latency in Treg cells and demonstrate ways to target virus reactivation for the purpose of eliminating the reservoir. First, we will define the level of cellular activation associated with latent Treg cell infection. Second, we will determine whether reactivation of virus from Treg cells requires entry into the cell cycle. And finally, we will define the role of the MAPK/ERK signal transduction pathway in Treg cell HIV-1 virus reactivation in an effort to understand mechanistically how we can safely purge the Treg cell reservoir of latent virus. PUBLIC HEALTH RELEVANCE: HIV currently infects greater than 40 million people worldwide and the infection rate is disproportionately higher in minorities and women. Our greatest challenge in controlling and eventually eradicating HIV infection is viral latency. Through the use of a primary cell model of infection and cells derived from HIV+ patients, we seek to define the mechanisms by which latency is established and virus is reactivated in Regulatory T cells.